02 Jul Bloodcenter of Wisconsin's new genetic test identifies people at high risk for developing inherited form of leukemia

BloodCenter of Wisconsin’s Diagnostic Laboratories has announced that it is the first laboratory in the United States to develop and offer a genetic test, known as “CEBPA Mutation Analysis,” for inherited acute myeloid leukemia (AML). AML is the second most common form of leukemia.
The link between inherited variants in the CEBPA gene and the familial form of acute myeloid leukemia (AML) was first described in the New England Journal of Medicine in 2004. This relationship has subsequently been confirmed in several published reports. Almost all patients found to have inherited CEBPA mutations have had leukemia. Therefore, germline CEBPA mutations appear to predict the development of leukemia in individuals who lack manifestations of the disease.
Family members of an AML patient who carries an inherited CEBPA mutation can be tested for the presence of this mutation with BloodCenter’s new DNA-based test. Those in whom the CEBPA mutation is detected can be monitored by their physicians for signs and symptoms of leukemia. Earlier detection of the cancer in these patients could result in more rapid treatment, and potentially produce better outcomes. AML patients and their relatives can also utilize this information in family planning decisions.
“CEBPA-related familial AML is rare, but the incidence may be larger than we believe because the medical community hasn’t been able to look for it,” said Roger D. Klein, M.D., J.D., BloodCenter’s Medical Director of Molecular Oncology.Methodology and Limits
Inherited CEBPA mutations are detected and characterized by a combination of PCR amplification and direct sequencing of the coding and junctional regions of the CEBPA gene. The assay is expected to detect >99% of germline variants that are found within these areas.
“Failing to detect a variant does not mean with 100 percent certainty that there is not a problem with the gene,” added Dr. Klein. “For example, one could have a disease-causing mutation in a promoter region that is important to the gene’s function, or one could have a complete deletion of the gene. This assay would not detect either of these unusual types of mutations. Therefore, we will caution referring physicians and genetic counselors that a negative result is not an absolute guarantee that a family does not carry an inherited CEBPA mutation. However, CEBPA Mutation Analysis is extremely accurate for finding variants in the coding and junctional regions of the gene, which is where most disease-related mutations are likely to occur.”Assay Variant Aids Risk Stratification for Larger AML Population
In addition, BloodCenter offers a modified version of CEBPA Mutation Analysis for non-inherited (sporadic) AML. This test is performed on DNA from the leukemia cells, rather than normal blood cells as in the test for inherited leukemia. In 15 – 18% of cases of a type of sporadic AML called “AML with normal cytogenetics” (CN-AML), CEBPA mutations serve as a biomarker that is associated with relatively favorable outcomes.
CN-AML accounts for about 50% of all AML. BloodCenter is also believed to be the first laboratory in the United States to offer CEBPA testing for CN-AML.
“For sporadic AML cases, we add fragment analysis to examine the gene for alterations in its length. The combination of fragment analysis and direct sequencing allows us to improve the lower limit of detection of the assay. This is important in sporadic leukemia, where low levels of a mutation may be present. By contrast, inherited mutations are typically found in a 50:50 ratio,” Dr. Klein said.
BloodCenter is considered a world expert in blood-related disorders due to a unique combination of medical and technical expertise that allows it to develop and interpret diagnostic assays for blood-related cancers. Dr. Klein believes that CEBPA Mutation Analysis is another important contribution to the oncology community. “This work is complex, which is why few labs test for rare genetic variants. With the knowledge gained through this assay, BloodCenter of Wisconsin will look to develop additional tests for inherited and sporadic blood malignancies. Each time we develop a genetic test, we are advancing the understanding of the genetics underlying blood cancers. We hope that what we learn will eventually contribute to better clinical outcomes.”